In cancer chemotherapy it is necessary to eradicate all tumor cells or the surviving cells will continue to replicate unchecked and the cancer will return. Toxic side effects of antineoplastic drugs impose a ceiling upon the intensity of dosing per treatment cycle. Each cycle in a program of treatment kills less than 99% of tumor cells and some regrowth of cancer cells occurs between cycles. The proportion of tumor cells killed in a treatment cycle typically remains constant throughout the program even when the disease responds well to the chemotherapy. It is therefore indicated in cancer chemotherapy to use the highest dose of an antineoplastic agent that a patient is able to tolerate and to administer the drug as frequently as possible. Goodman & Gilman's The Pharmacological Basis of Therapeutics 1230 (9th ed. 1996).
Many antineoplastic agents used in cancer chemotherapy are administered directly to the patient's bloodstream in order to bypass problems of absorption and pre-systemic metabolism. Intravenous delivery is not amenable to self administration in a home setting and usually necessitates hospitalization at least as an outpatient. Intraveneous dosing schedules, although of high intensity, are typically less frequent than they would be if the drug could be administered in a home setting by means other than intravenous injection. Chemotherapy with many antineoplastic agents could benefit from a higher frequency dosing schedule for better efficacy, in some cases in conjunction with lower dosing in order to reduce adverse effects.
Irinotecan (CPT-11) is an example of a drug that is currently administered by i.v. for which extended duration of therapy is more efficacious than higher dose intermittent therapy. Thompson, J. et. al. “Efficacy of oral irinotecan against neuroblastoma xenografts” Anti-Cancer Drugs (1997), 8, 313-332; Drengler, R. L. et. al., “Phase I and Pharmacokinetic Trial of Oral Irinotecan Administered Daily for 5 Days Every 3 Weeks in Patients with Solid Tumors”, Journal of Clinical Oncology (1999), 17, 685-696; Zamboni, W. C. et. al. “Studies of the Efficacy and Pharmacology of Irinotecan Against Human Colon Tumor Xenograft Models” Clin. Cancer Res. (1998), 4, 743-753.
Irinotecan is a water-soluble camptothecin derivative that interrupts DNA replication by binding to the topoisomerase I enzyme responsible for cutting and religating single DNA strands. Irinotecan is most effective against a particular tumor cell during the DNA synthesis phase of cell replication, making it a phase sensitive drug. Only a fraction of tumor cells are vulnerable to cell death during a treatment cycle with irinotecan because only a fraction will be caught in the susceptible phases of replication.
It has been shown in an animal model that lower dose daily administration of irinotecan is as effective and less toxic than less frequent higher dose administration. Houghton, P. J. et. al. “Efficacy of Topoisomerase I Inhibitors Topotecan and Irinotecan Administered at Low Dose Levels in Protracted Schedules to Mice Bearing Xenografts of Human Tumors” Cancer Chemother. Pharmacol. (1995), 36, 393-403; Thompson, J. et. al. “Efficacy of Systemic Administration of Irinotecan Against Neuroblastoma Xenografts” Clin. Cancer Res. (1997), 3, 423-432.
The greater efficacy of extended duration therapy and the reduced toxicity of lower dose daily administration make irinotecan an excellent candidate for oral delivery as a convenient way of achieving lower dose protracted schedules. Rothenberg, M. L. et. al. “Alternative Dosing Schedules for Irinotecan”, Oncology (1998), 8 suppl 6, 68-71.
Oral delivery, with the convenience of self administration and home dosing, would ease the burden on the patient and care giver imposed by a more frequent dosing schedule. However, the oral bioavailability of irinotecan is reported to be only about 20% of its iv. bioavailability. Kuhn, J. G., “Pharmacology of Irinotecan” Oncology(1998), 12 supp. 6, 39-42; Drengler, R. L., Ibid. Serious problems of absorption and pre-systemic metabolism of irinotecan need to be overcome before oral delivery becomes available as a treatment option.
Irinotecan is a metabolic precursor of 7-ethyl-10-hydroxycamptothecin. The metabolite is also known by the designation SN-38. SN-38 has been found to be approximately a thousand times more potent an inhibitor of topoisomerase I than irinotecan. SN-38 is formed by hydrolysis of the ester side chain of irinotecan by carboxylesterases in the body. Steward, C. F. et. al., “Disposition of Irinotecan and Sn-38 Following Oral and Intravenous Irinotecan Dosing in Mice” Cancer Chemother. Pharmacol. (1997), 40, 259-265; Kuhn, J. G., “Pharmacology of Irinotecan” Oncology (1998), 12 supp. 6, 39-42. While the main site of metabolism of irinotecan to the more active SN-38 is the liver, there is considerable activity of carboxylesterase in the upper GI tract. Kuhn, J. G. Ibid; Takamura, K. et. al., “Involvement of Beta-glucuronidase in Intestinal Microflora in the Intestinal Toxicity of the Anti Tumor Camptothecin Derivative Irinotecan Hydrochloride (CPT-11) in Rats” Cancer Res. (1996), 56, 3752-3757.
Both irinotecan and SN-38 can exist in a closed ring lactone form and an open, hydroxy acid form. Only the lactone form of either compound is active against tumors. Steward, C. F. et. al. Ibid; Drengler, R. L. et. al. Ibid. Acidic conditions favor the lactone form of the drug. Basic conditions favor the hydroxy acid form.
If irinotecan can be released in the stomach, the low gastric pH will keep more of the irinotecan in the active lactone form. Therefore, more of the SN-38 that is produced by carboxylesterases in the gut should be in the active lactone form. Steward, C. F. et. al. Ibid; Drengler, R. L. et. al. Ibid. This assumption of a higher ratio of active SN-38 to inactive SN-38 by oral delivery has been borne out in animal models and in a human phase I study. Zamboni, W. C. et. al. Ibid; Kuhn J. G. Ibid; Drengler, R. L. et. al. Ibid. Delivery and absorption of the irinotecan preferentially in the stomach should improve its oral systemic bioavailability against tumor cells by increasing the proportion of SN-38 that reaches the tumor in active form.
Other cell cycle specific drugs are likely to benefit from more frequent dosing which extends the duration of drug presentation to the tumor and catches more of the cells in the sensitive phase of their cycle. The benefit can be realized whether they be of the topoisomerase mechanism or other phase sensitive mechanism (e.g. paclitaxel which works by stabilizing microtubule polymerization). Etoposide and paclitaxel are two other phase sensitive antineoplastic agents that could be used more efficaciously with frequent lower oral dosing as opposed to intermittent higher dosing by i.v. Etoposide binds to topoisomerase II and DNA resulting in double stranded DNA breaks that a cell cannot repair. Etoposide undergoes highly variable absorption when administered orally and exhibits on average about 50% of its i.v. potency. Goodman & Gilman's The Pharmacological Basis of Therapeutics 1262 (9th ed. 1996). Paclitaxel is not currently administered orally.
One of the factors that causes the low oral bioavailability of etoposide and paclitaxel is removal by the P-glycoprotein (“Pgp”) efflux pump mechanism of cells at the site of intestinal absorption. Lo, Y. L.; Huang, J. D., “Comparison of Effect of Natural or Artificial Rodent Diet on Etoposide Absorption in Rats” In Vivo (1999), 13, 51-55; Britten, C. D. et. al., “Oral Paclitaxel and Concurrent Cyclosporin A: Targeting Clinically Relevant Systemic Exposure to Paclitaxel” Clin. Cancer Res. (2000), 6, 3459-3468; Fromm, M. F., “P-glycoprotein: a Defense Mechanism Limiting Oral Bioavailability and CNS Accumulation of Drugs” Int. J. Clin. Pharmacol. Ther. (2000), 38, 69-74; Terwogt, J. M. M., et. al. “Co-administration of Oral Cyclosporin a Enables Oral Therapy with Paclitaxel” Clin Cancer Res (1999), 5, 3379-3384; Sparreboom, A. et. al. “Limited Oral Bioavailability and Active Epithelial Excretion of Paclitaxel (Taxol) Caused by P-glycoprotein in the Intestine” PNAS (1997), 94, 2031-2035.
Pgp efflux pump activity is also relevant to other antineoplastic agents such as doxorubicin and vincristine and to anti-HIV drugs. Lum, B. L.; Gosland, M. P., “MDR Expression in Normal Tissues: Pharmacologic Implications for the Clinical Use of P-glycoprotein Inhibitors” Hematol Oncol. Clin. North Am. (1995), 9, 319-336; Aungst, B. J., “P-glycoprotein, Secretory Transport, and Other Barriers to the Oral Delivery of Anti-hiv Drugs” Adv. Drug Deliv. Rev. (1999), 39, 105-116.
Research is underway to develop new agents that are not susceptible to p-glycoprotein efflux and to develop agents that inhibit the Pgp efflux pump. Morseman, J. M.; McLeod, H. L., “Taxane Chemotherapy and New Microtubule-Interactive Agents” Curr. Opin. Oncol. Endro. Metab. Invest. Drugs (2000), 2, 305-311; Polizzi, D. et. al., “Oral Efficacy and Bioavailability of a Novel Taxane” Clin. Cancer Res. (2000), 6, 2070-2074; Nicoletti, M. I. et. al. “IDN5109, a Taxane with Oral Bioavailability and Potent Antitumor Activity” Cancer Res. (2000), 60, 842-846; Sikic, B. I., Ibid; Mistry, P., Ibid; Millward, M. J.; Lieu, E. A.; Robinson, A.; Cantwell, B. M. J., “High Dose Tamoxifen with Etoposide: a Study of a Potential Multi-drug Resistance Modulator” Oncology-Switzerland (1994), 51, 79-83; Raderer, M.; Scheithauer W., “Clinical Trials of Agents That Reverse Multi-drug Resistance: a Literature Review” Cancer (1993), 72, 3553-3563; Britten, C. D., Ibid; Tai, H. L., “Technology evaluation: Valspodar, Novartis AG” Curr. Opin. Mol. Ther. (2000), 2, 459-467; Terwogt, J. M. M., Ibid.
However, new agents are not a timely solution to the problem of pre-systemic deactivation and Pgp efflux pump removal. Development and testing of new agents, whether anti-cancer agents that are unaffected by the efflux pump or blockers of the efflux pump, will take many years with unpredictable results in terms of efficacy and adverse events. The use of known potent efflux pump blocking agents like cyclosporin, tamoxifen, verapamil in cancer chemotherapy exposes the body to the known potent effects of these drugs as well as their adverse event profiles, all as side effects of the efflux pump blocking.
If drug delivery could be used with the known effective antineoplastic agents to minimize the effects of the Pgp pump, improved oral administration could be realized without the disadvantages described above and without high concomitant doses of Pgp efflux pump blocker drugs.
Some cells that are resistant to etoposide demonstrate amplification of the MDR-1 gene that encodes the Pgp drug efflux transporter. Lowe et. al. Cell, 1993, 74, 957-967. The Pgp efflux pump also has been found in tumor cells. Sikic, B. I., “Modulation of Multidrug Resistance: a Paradigm for Translational Clinical Research” Oncology (1999) 13 A, 183-189; Mistry, P. et. al. “In Vivo Efficacy of Xr9051, a Potent Modulator of P-glycoprotein Mediated Multidrug Resistance” Br. J. Cancer (1999) 79, 1672-1678; Naito, M.;Tsuro, T., “Therapeutic Approach to Drug Resistant Tumors” Ther Drug Monit (1998), 20, 577-580.
However, Pgp expression was consistently found to be low in the stomach cells of five mammalian species. Beaulieu, E; Demeule, M.; Jette, L.; Beliveau, R., “Comparative Assessment of P-glycoprotein Expression in Mammalian Tissues by Immunoblotting” Int. J. Bio Chromatog (1999), 4, 253-269. Oral administration and absorption of etoposide, paclitaxel, doxorubicin and vincristine preferentially in the stomach should improve their systemic bioavailability.
Cancer chemotherapy with antineoplastic agents whose oral effectiveness is limited by pre-systemic and systemic deactivation or removal would greatly benefit if the antineoplastic agent could be administered orally and then released in the patient'sstomach so that it would be absorbed predominantly from the patient's stomach, jejunum or duodenum.
Pharmaceutical formulation specialists have developed techniques for retaining drugs in a patient's stomach over time. One of the general techniques is intragastric expansion, wherein expansion of the dosage form prevents it from passing through the pylorus. The diameter of the pylorus varies between individuals from about 1 to about 4 cm, averaging about 2 cm. An expanding gastric retention dosage form must expand to at least 2 cm×2 cm in two dimensions to cause gastric retention, though a size of 2.5 cm×2 cm is more desirable.
One type of intragastric expanding dosage form uses hydrogels to expand the dosage form upon contact with gastric fluid to sufficient size to prevent its passage through the pylorus. An example of such a dosage form is described in U.S. Pat. No. 4,434,153. The '153 patent discloses a device for executing a therapeutic program after oral ingestion, the device having a matrix formed of a non-hydrated hydrogel and a plurality of tiny pills containing a drug dispersed throughout the matrix.
One of the major problems with intragastric expanding hydrogels is that it can take several hours for the hydrogel to become fully hydrated and to expand to sufficient size to cause it to be retained in the stomach. Hwang, S. et al. “Gastric Retentive Drug-Delivery Systems,” Critical Reviews in Therapeutic Drug Carrier Systems, 1998, 15, 243-284 Since non-expanding dosage forms remain in the stomach on average for about 1 to 3 hours, there is a high probability that known expanding dosage forms like that of the '153 patent will pass through the pylorus before attaining a sufficient size to obstruct passage. The rate-limiting factor in the expansion of ordinary hydrogels is the rate of diffusion of water to non-surfacial hydrogel material in the dosage form. Conventional hydrogels are not very porous when they are dry, so transport of water into the hydrogel can be slow. In addition, a low permeability gelatinous layer forms on the surface of wetted hydrogel, which further slows transport of water into the hydrogel.
One approach to solving the problem of slow expansion has been the development of superporous hydrogels. Superporous hydrogels have networks of pores of 100 μm diameter or more. At that diameter, the pores are able to rapidly transport water deep into the superporous hydrogel by capillary action. Water reaches the non-surfacial hydrogel material quickly resulting in a rapid expansion of the superporous hydrogel to its full extent. Superporous hydrogels are still under development and have not been approved for pharmaceutical use by the U.S. Food and Drug Administration. There are also shortcomings attendant to the use of superporous hydrogels. They tend to be structurally weak and some are unable to withstand the mechanical stresses of the natural contractions that propel food out of the stomach and into the intestine. The superporous hydrogels tend to break up quickly into particles too small to be retained.
Chen, J. and Park, K. Journal of Controlled Release 2000, 65, 73-82, describes a superporous hydrogel whose mechanical strength is improved by the polymerization of precursor hydrogel monomers in the presence of several superdisintegrants. The result of the polymerization described by Chen and Park is a substance having interconnecting cross-linking networks of polyacrylate and, e.g., cross-linked carboxymethyl cellulose sodium. Such interconnecting networks are not expected to have the same physical properties as conventional hydrogels made from the same precursor hydrogel monomers.
Another general strategy for retaining dosage forms in the stomach is intragastric floatation, as exemplified in U.S. Pat. Nos. 4,140,755 and 4,167,558. Intragastric floatation systems are less dense than gastric fluid and avoid passage through the pylorus by floating on top of the gastric fluid. These systems generally take one of three forms. Hydrodynamically balanced floating systems comprise capsules of the active ingredient and a hydrogel that forms a gelatinous coating upon contact with water that slows further uptake of water. In one example of such a system, a capsule containing the non-hydrated hydrogel and an active ingredient dissolves upon contact with gastric fluid. The hydrogel then comes into contact with gastric fluid and forms a gelatinous coating on the surface. The gelatinous coating traps air inside the hydrogel thereby making the mass buoyant. Expansion of the hydrogel also makes it less dense and therefore more buoyant. Another form of intragastric floatation system is a gas generating system, which evolves gas upon contact with water. Gas bubbles trapped in the dosage form make it buoyant. Another variation on the intragastric floatation systems are low density core systems, wherein the active ingredient is coated over a low density material like puffed rice.
The floating dosage forms and expanding dosage forms previously described operate by different gastric retention mechanisms, each with its own requirements to be effective. A floatation system must remain buoyant even while absorbing gastric fluid. An expanding system must expand rapidly to a size sufficient to obstruct transit into the intestine and yet be small enough in its non-hydrated state to be swallowed.
The present invention includes dosage forms for gastric delivery of antineoplastic agents in embodiments wherein the dosage form expands as well as in embodiments wherein the dosage form expands and generates gas for floatation.